This invention relates to novel 2-azetidinecarboxylic acid derivatives having neurotrophic activity. These compounds, along with related compositions and methods, are useful in the treatment and prevention of neuronal disorders such as Parkinson""s disease, Alzheimer""s disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy and Bell""s palsy.
Neurodepenerative Diseases
Neurodegenerative diseases constitute a major threat to public health throughout the world. One of the most serious such diseases is Alzheimer""s disease (xe2x80x9cADxe2x80x9d), a major cause of dementia in aged humans and the fourth most common medical cause of death in the United States. In the U.S., it is estimated that AD afflicts two to three million individuals overall, and more than 5% of the population over the age of 65. Although the exact etiology of AD remains to be defined, the disease is characterized by the presence of a large number of amyloid plaques and neurofibrillary tangles in regions of the brain involved in cognitive function, and degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas. Currently, there are no effective therapies for AD. Brinton, R. D. and Yamazaki, R. S., Pharm. Res., 1998, 15, 386-398.
Similar to AD, Parkinson""s Disease (xe2x80x9cPDxe2x80x9d) is a progressive degenerative disease of the central nervous system (xe2x80x9cCNSxe2x80x9d). The lifetime incidence of the disease is approximately 2% in the general population. In PD, degeneration of the dopaminergic neurons of the substantia nigra leads to a decrease in dopamine levels in the region of the brain controlling voluntary movement, the corpus striatum. Therefore, standard treatments have focused on the administration of agents, like L-dopa and bromocriptine, which replenish dopamine levels in the affected areas of the brain. Dopaminergic regimens lose their efficacy, however, as nerve cells continue to die and the disease progresses. At the same time, the involuntary tremors seen in the early stages of PD advance to periods of difficult movement and, ultimately, to immobility. Therefore, alternative therapies are actively being sought. Pahwa, R. and Koller, W. C., Drugs Today, 1998, 34, 95-105.
Neurodegenerative diseases of the somatosensory nervous system also constitute a class of debilitating and potentially lethal conditions. Amyotrophic lateral sclerosis (xe2x80x9cALSxe2x80x9d) is a fatal disease characterized by progressive degeneration of the upper and lower motor neurons. Although the precise etiology of ALS is unknown, popular theories suggest that excitotoxicity and/or oxidative stress are contributing factors. Riluzole is the first drug approved and marketed for ALS. It possesses antiexcitotoxic properties and has been shown to increase the rate of survival of ALS patients. However, the drug is not a cure, and clinical trials of alternative agents are currently underway. Louvel, E., Hugon, J. and Doble, A., Trends Pharmacol. Sci., 1997, 18, 196-203.
Peripheral neuropathies are secondary to a number of metabolic and vascular conditions. In particular, approximately 30% of patients with diabetes mellitus suffer from some form of peripheral neuropathy that may affect the small myelinated fibers, causing loss of pain and temperature sensation, or the large fibers, causing motor or somatosensory defects. Pharmacotherapeutic intervention tends to be symptomatic, and the best approach to treatment and prevention remains the maintenance of normal blood glucose levels through diet and insulin administration. Biessels, G. J. and Van Dam, P. S., Neurosci. Res. Commun., 1997, 20, 1-10.
A considerable body of evidence now suggests that deficiencies in the levels of certain proteinaceous growth factors, or neurotrophic factors, may play key pathoetiological roles in both peripheral and central neurodegenerative diseases. Tomlinson, D. R., Fernyhough, P. and Diemel, L. T. Diabetes, 1997, 46(suppl. 2) S43-S49; Hamilton, G. S., Chem. Ind., (London) 1998, 4,127-132; Louvel, E., Hugon, J. and Doble, A., Trends Pharmacol. Sci., 1997, 18, 196-203; Ebadi, M., et al., Neurochem. Int., 1997, 30, 347-374.
These neurotrophic factors can be divided into two structural classes: (1) the neurotrophins, including nerve growth factor (xe2x80x9cNGFxe2x80x9d), glial cell-derived neurotrophic growth factor (xe2x80x9cGDNFxe2x80x9d), brain-derived neurotrophic factor (xe2x80x9cBDNFxe2x80x9d), neurotrophin 3 (xe2x80x9cNT-3xe2x80x9d), neurotrophin 4/5 (xe2x80x9cNT-4/5xe2x80x9d), and neurotrophin 2 (xe2x80x9cNT-2xe2x80x9d); and (2) ciliary neurotrophic factor (xe2x80x9cCNTFxe2x80x9d) which is related to the cytokine family of molecules. All neurotrophic factors promote neurite outgrowth, induce differentiation, and suppress programmed cell death or apoptosis in specific subpopulations of peripheral and central neurons. For example, NGF exerts trophic effects on sympathetic and sensory neurons of the dorsal root ganglion and cholinergic neurons of medial septum in the CNS, suggesting potential therapeutic utility in AD. CNTF has trophic actions on a broad cross-section of neurons, including parasympathetic, sensory, sympathetic, motor, cerebellar, hippocampal, and septal neurons. Of particular interest is the fact that CNTF partially prevents the atrophy of skeletal muscle following nerve lesioning but has no effect on innervated muscle, indicating that CNTF is primarily operative in the pathological state. As a result, CNTF is currently being evaluated for its effects in musculoskeletal diseases like ALS.
The clinical utility of proteinaceous neurotrophic agents is severely hampered by their limited bioavailability, especially in the CNS. This necessitates the administration of these agents directly into the brain to induce a therapeutic effectxe2x80x94a relatively hazardous and cumbersome route of administration.
Chemical Agents
U.S. Pat. No. 5,294,603 to Rinehart discloses several didemnin derivatives in which proline in position 8 is replaced with L-azetidine-2-carboxylic acid. These synthetic didemnin derivatives are described as exhibiting antiviral, cytotoxic and immunosuppressive activities. Among the intermediates in the synthesis of these analogs are compounds wherein R is hydrogen or benzyl, having the following general structure: 
Lyons, W. E., et al. (Proc. Natl. Acad. Sci., 1994, 91(8), 3191-5) describe the neurotrophic effects of the immunosuppressant drug FK506, which shows neurotrophic activity in cultures of PC12 cells and sensory ganglia: 
Vertex Pharmaceuticals, Inc. (xe2x80x9cVertexxe2x80x9d) in a South African Application 964852, discloses compounds that are described as useful for inhibiting the rotamase activity of the FKBP12 immunophilin and stimulating neurite outgrowth in cell cultures. These compounds are typified by the following structure: 
Vertex PCT Application WO 92/19593 discloses a series of compounds that are described as useful for inhibiting the rotamase activity of FK506-binding proteins (xe2x80x9cFKBPxe2x80x9d) and inhibiting T cell activation. These compounds are exemplified by the following structure: 
Vertex PCT Application WO 94/07858 discloses a series of compounds that are described as useful multi-drug-resistant cancer cell-sensitizers for maintaining, increasing or restoring the sensitivity of cells to therapeutic or prophylactic agents. The compounds are exemplified by the following structure: 
Patents collectively to Guilford Pharmaceuticals, Inc., GPI NIL Holdings, Inc. and Johns Hopkins University School of Medicine (collectively xe2x80x9cGuilfordxe2x80x9d) disclose compounds that are described as useful for inhibiting the activity of FKBP-type immunophilins, stimulating neuronal growth and regeneration, and treating neurological disorders.
In particular, Guilford U.S. Pat. No. 5,696,135 and PCT application WO 96/40140 disclose a method of using pipecolic acid derivative compounds, related to FK506 and rapamycin, to treat a neurological disorder in an animal. The compounds therein are described as useful for inhibiting the rotamase activity of an FKBP-type immunophilin, stimulating neuronal growth in chick dorsal root ganglion in vitro, and promoting repair of lesioned sciatic nerves in rats.
Guilford U.S. Pat. No. 5,798,355 discloses a method of using macrocyclic and acyclic pipecolic acid derivatives, which it describes as inhibiting the enzyme activity of FKBP-type immunophilins and stimulating neuronal growth and regeneration.
Guilford U.S. Pat. Nos. 5,614,547 and 5,795,908, and PCT application WO 96/40633, disclose a series of N-glyoxyl-prolyl ester compounds that are described as useful for inhibiting the rotamase activity of the FKBP-12 immunophilin, promoting neuronal growth and regeneration, and treating neurological disorders. The compounds are typified by the following structure: 
Guilford U.S. Pat. No. 5,801,197 and PCT application WO 97/16190 disclose a series of nonimmunosuppressive pipecolic acid derivatives that are described as useful for the treatment of damaged nerves in animals. The following are representative analogs of the series: 
Guilford U.S. Pat. No. 5,721,256 discloses compounds that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal. The series of sulfonamide compounds are typified by the following structure: 
Guilford U.S. Pat. No. 5,801,187 and PCT application WO 98/13355 disclose a series of heterocyclic ester and amide compounds that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal. The compounds are typified by the following structure: 
Guilford PCT Application WO 98/13343 discloses a series of heterocyclic thioester and ketone compounds that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal. The compounds are exemplified by the following structure: 
Guilford PCT Application WO 98/29116 discloses a series of N-linked sulfonamide compounds of heterocyclic thioesters that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal. The compounds are typified by the following structure: 
Guilford PCT Application WO 98/29117 discloses a series of N-linked ureas and carbamate compounds of heterocyclic thioesters that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal. The compounds are typified by the following structure: 
Guilford PCT Application WO 98/37882 discloses a method of using small molecule carbamate and urea compounds that are described as useful for inhibiting the rotamase activity of FKBP-type immunophilins and stimulating neuronal growth and regeneration. The compounds are typified by the following structure: 
Guilford PCT Application WO 98/37885 discloses a series of N-oxide compounds of heterocyclic esters, amides, thioesters and ketones that are described as useful for inhibiting the rotamase activity of FKBP, promoting neuronal growth and regeneration and treating neurological disorders in an animal. The compounds are typified by the following structure: 
Guilford PCT Application WO 98/25950 discloses a series of tetra- and pentapeptide compounds containing at least two proline residues, which compounds are described as useful for inhibiting the rotamase activity of cyclophilin, promoting neuronal growth and regeneration, and effecting neuronal activity in an animal.
None of the known agents discussed herein has ever been demonstrated as having therapeutic or prophylactic efficacy against neurodegenerative disorders in humans. Thus, there exists a strong and unmet need for agents having such efficacy.
This invention provides a compound having the structure: 
or a pharmaceutically acceptable salt thereof, wherein
(a) R1 is selected from the group consisting of:
(i) COCOR2, wherein R2 is (C1-C6)-straight or branched alkyl, (C1-C6)-straight or branched alkenyl, (C5-C7)cycloalkyl, 2-thienyl, 3-thienyl, phenyl, or substituted phenyl (the substituted phenyl ring having one to three substituents independently selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halogen),
(ii) CONHR3, wherein R3 is (C1-C6)-straight or branched alkyl,
(iii) SO2R4, wherein R4 is phenylalkyl or substituted phenylalkyl (the substituted phenyl ring having one to three substituents independently selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halogen), and
(iv) 
xe2x80x83wherein the ring portion thereof is aromatic and optionally contains one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
(b) X and Y are (i) Cxe2x95x90O and (ii) O or NR5 (wherein R5 is (C1-C6)-straight or branched alkyl), respectively, or alternatively together form a 1,5-disubstituted tetrazole ring;
(c) Z is (C1-C5)-straight or branched alkyl or alkenyl substituted in one or more positions with Ar, which Ar is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, phenyl and substituted phenyl (the substituted phenyl ring having from one to three substituents independently selected from the group consisting of lower alkyl, lower alkoxy, hydroxy and halogen), with the proviso that Z and R2 cannot both be C1-alkyl; and
(d) A is Xxe2x80x94Yxe2x80x94Z or hydrogen.
This invention also provides a method of stimulating neuronal growth comprising contacting neurons with an effective amount of the instant compound. This invention further provides a pharmaceutical composition comprising one of the instant compounds and a pharmaceutically acceptable carrier.
This invention still further provides a method of treating a subject afflicted with a disorder characterized by neuronal damage caused by disease or trauma, comprising administering to the subject a therapeutically effective amount of the instant pharmaceutical composition. Finally, this invention provides a method of inhibiting in a subject the onset of a disorder characterized by neuronal damage caused by disease, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition.